八宝丹抑制炎症相关肝癌发生发展的机制研究

Inflammatory microenvironment plays an important role in the development of hepatocellular carcinoma (HCC) and the microenvironment modification is expected to become a new strategy for the prevention and therapy of HCC. However, due to the complicated inflammatory microenvironment, the strategy by regulating single inflammatory cell or factor is hard to get ideal result for inhibiting HCC development. Chinese traditional medicine has the advantages of multiple targets and multidirectional adjustment. Babao Dan (BBD), as a Chinese traditional medicine, is known as the potential of anti-inflammation and liver function protection. Our previous study demonstrated that BBD could inhibit the incidence and development of HCC in rat. However, the underlying mechanism of is still unknown. Based on the Inflammatory microenvironment plays an important role in the development of hepatocellular carcinoma (HCC) and the microenvironment modification is expected to become a new strategy for the prevention and therapy of HCC. However, due to the complexity of inflammatory microenvironment, the strategy by regulating single inflammatory cell or factor is hard to get ideal result for inhibiting HCC development. Chinese traditional medicine has the advantages of multiple targets and multidirectional adjustment. Babao Dan (BBD), as a Chinese traditional medicine, is known as the potential of anti-inflammation and liver function protection. Our previous study demonstrated that BBD could inhibit the incidence and development of HCC in rat. However, the underlying mechanism is still unknown. Based on the HCC animal model, the effect of BBD on the development of HCC will be observed by administrating BBD at different time stage of HCC. Then, we will screen out the key inflammatory cells and factors by analyzing the profile of inflammatory cells and factors in different stage of HCC with or without BBD administration. Furthermore, we will clarify the mechanism of BBD in inhibiting the development of HCC by exploring the role of BBD in inhibiting relative inflammatory cell and in inhibiting malignant transformation of normal hepatocytes and malignant proliferation of HCC cells induced by relative inflammatory cytokines. The results will not only help us to understand the underlying mechanism of inflammation in the development of HCC, but also provide a new direction and research basis for BBD using in HCC therapy.

炎症微环境在影响肝癌发生发展中具有重要作用，基于炎症微环境调控的肝癌防治新策略越来越受到关注。然而由于炎症微环境的复杂性，单一炎症细胞或因子调控难以获得理想疗效。传统中药具有多靶点和多向调节的优势，八宝丹是我国传统中药中一种具有确切疗效的复方抗炎保肝药物。我们前期在大鼠原发性肝癌模型中发现八宝丹对于肝癌的发生和发展具有显著的抑制作用，但具体机制尚不清楚。本课题拟利用大鼠原发肝癌模型，在诱癌的不同阶段给予八宝丹干预，观察八宝丹对肝癌发生发展的影响；通过研究诱癌不同阶段相关炎症细胞和炎症因子的变化，明确八宝丹抑炎的关键作用细胞和因子；再通过体内外实验观察八宝丹对靶细胞功能的影响及炎症因子对正常肝细胞恶性转化及肝癌细胞恶性增殖的影响，阐明八宝丹通过抑制炎症达到抑制肝癌发生发展的具体机制。预期结果有助于我们加深对炎症在肝癌发生发展中作用机制的认识，也为八宝丹更为有效地应用于肝癌治疗提供理论依据。

炎症微环境在影响肝癌发生发展中具有重要作用，基于炎症微环境调控的肝癌防治新策略越来越受到关注。然而由于炎症微环境的复杂性，单一炎症细胞或因子调控难以获得理想疗效。传统中药具有多靶点和多向调节的优势，八宝丹是我国传统中药中一种具有确切疗效的复方抗炎保肝药物。我们研究发现八宝丹可通过抑制肝脏炎症反应起到抑制肝癌发生的作用，其机制可能是通过对TLR4及其下游信号分子MyD88和TRAF6的抑制，降低炎症因子的表达，减少炎症浸润，改善肝脏微环境，减少肝前体细胞激活和异常分化。在肝癌形成后，八宝丹同样可显著抑制肝癌发展，延长大鼠生存期。相关机制可能是八宝丹通过抑制巨噬细胞的TLR4表达及其下游信号分子MyD88和TRAF6信号通路，从而减少巨噬细胞向M2分型的转化，减少炎症反应及炎症因子分泌，抑制肝癌的进展。此外，我们还观察了八宝丹对酒精性肝损伤和非酒精性脂肪肝的治疗作用。发现八宝丹可对急性酒精性肝损伤具有保护作用，其作用机制可能是：一方面抑制CYP2E1的表达，另一方面能够启动Nrf2基因及其下游基因序列的表达，从而抑制氧化应激作用和促进相关抗氧化物的生成。八宝丹还可以通过调节脂质相关合成基因及脂肪酸氧化基因的表达抑制高脂饮食引起的脂肪肝进展和肝功能指标异常，改善肝脏和血清中炎症因子的表达，改善肝脏纤维化。相关研究结果有助于我们加深对炎症在肝癌发生发展中作用机制的认识，也为八宝丹更为有效地用于炎症相关肝癌治疗提供理论依据。